1. Field of the Invention
The present invention relates generally to the field of treatments for the prevention and/or healing of cardiac tissue against heart failure or ischemic conditions and the manipulation of cardiac cells in vivo or in vitro.
2. Related Art
Heart failure (HF) is a progressive condition in which the heart can no longer pump enough blood to the rest of the body. There can be many causes of heart failure in individuals. Common causes of heart failure may include myocardial infarction (heart attacks) and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy.
For example, dilated cardiomyopathy (DCM) is a heterogenous group of inherited and acquired disease characterized by cardiac dilation and reduced systolic function, usually evident in the second or third decade of life. Adult and childhood forms of DCM may be primary or idiopathic (50-70%), or secondary to sarcomeric gene mutations. DCM is an important and common cause of acute and chronic heart failure (HF), but also exhibits many pathophysiological features, such as loss of ventricular mass and replacement fibrosis, typical of HF of diverse causation, including end-stage ischemic cardiomyopathy. DCM is characterized by enlargement of the cardiac chambers, decreased myocardial contractility and unspecific histopathological findings, such as myocyte loss, increased apoptosis and interstitial fibrosis. Mutations associated with DCM have been identified in genes including β-MHC, cMyBPC, cardiac actin, cTnT, cTnI, and cTnC among others.
Doxorubicin is an effective and frequently used chemotherapeutic agent for various malignancies. The major limitation of this class of highly effective chemotherapeutic drug is its dose-dependent cardiotoxicity, resulting in the death of cardiomyocytes which often leads to irreversible myocardial dysfunction. Doxorubicin-induced cardiomyopathy (DOXO-DCM) is a specific and lethal complication of chronic doxorubicin therapy for which there is no treatment other than transplantation. Although DOXO-DCM is a specific form of DCM, it shares many unifying pathophysiological features with DCM of diverse causation, including the findings of extensive fibrosis, fibroblast proliferation, and myocytic and myofibril loss, in association with dilated phenotype and profound biventricular dysfunction. Purported mechanisms of DOXO DCM include excessive oxidative stress, myocyte apoptotic loss, and down-regulation of contractile genes such as myosin light and heavy chains, troponin-I, and desmin proteins. Although anti-oxidants and vincristine have demonstrated various degrees of efficacy in murine models of DOXO cardiotoxicity, there are currently no non-toxic, clinically viable drugs available for this indication, and clinical evidence of congestive heart failure usually denotes a lethal outcome without transplantation.
Childhood idiopathic DCM is a rare but highly debilitating disease of multiple causes with profound morbidity and mortality. The 1- and 5-year rates for death or transplantation for children with DCM based on National Heart, Lung, and Blood Institute's Pediatric Cardiomyopathy Registry are 39% and 53%, respectively, illustrating the inadequacy of current medical therapy. In 40% of children with symptomatic DCM, medical therapy fails within 2 years of diagnosis. The treatment for advanced heart failure resulting from childhood (and adult) DCM may involve escalating inotropic therapy, ventilation, and ultimately, deployment of ventricular assist devices (VADs) as a bridge to transplantation.
Currently there is no mechanism-based treatment available for Heart Failure, irrespective of etiology so that the prognosis of patients with chronic HF remains poor. New advances in the treatment of patients with DCM in the last decade rely on indirect methods to improve cardiac function, such as the combined use of angiotensin converting enzyme (ACE) inhibitors, angiotensin Π receptor (AR) antagonists, β-blockers, aldosterone antagonists and diuretics. Consequently, HF related mortality remains elevated, approaching 50% at 5 years in symptomatic patients, and constitutes, by disease category, a huge economic health care burden worldwide. Non-pharmacologic therapies, such as heart transplantation and the use of implantable assist devices, are considered only in the later stages of the disease, and access to such therapies is restricted to a fraction of patients who need them.
Thus, there continues to be an urgent need for the development of novel and specific anti-heart failure treatments for advanced heart failure of diversified etiologies.